Cough is the most common reason why sick patients visit physicians in the US. The long-range goal of this research is to delineate the neurogenic mechanisms by which cough is produced and regulated. The central hypothesis of this research is that the cough motor pattern is produced by an assembly of components that includes a novel regulatory element responsible for controlling the behavior of a reconfigured respiratory pattern generator. Moreover, the novel regulatory components that control laryngeal and tracheobronchial cough are not identical. The rationale for the proposed research is that once the functional organization of the brainstem cough pattern generation system is established, the mechanisms responsible for the production of pathological cough can be identified. The specific aims of the project are: 1) Determine the role of modulation of the expiratory phase in the regulation of the tracheobronchial and laryngeal cough motor patterns, 2) Determine the functional organization of the central regulatory system for tracheobronchial and laryngeal cough, 3) Determine the role of brainstem expiratory motor pathways in the antitussive-sensitive regulatory system for tracheobronchial cough, 4) Determine the role of spinal expiratory motor pathways in the antitussive-sensitive regulatory system for cough. In the first aim, key regulatory mechanisms controlling the frequency and magnitude of repetitive tracheobronchial and laryngeal cough will be determined by altering of the excitability of each. Our preliminary data suggest a) that the frequency of repetitive coughing is primarily controlled by modulation of the duration of the latter part of the cough expiratory phase, and b) that separate regulatory mechanisms are responsible for the control of the frequency and intensity of repetitive coughing. In support of the second aim, preliminary findings suggest differential sensitivity of tracheobronchial and laryngeal cough to antitussive drugs and thus divergent central regulatory mechanisms for each. In the third aim, we test a model that predicts the presence of a tracheobronchial cough gating mechanism that is presynaptic to medullary and spinal expiratory motor pathways. This gating mechanism is sensitive to antitussive drugs. The sensitivity of rostral and caudal medullary expiratory neurons to antitussive drugs will be determined during breathing and cough to differentiate between inhibition or disfacilitation of these neurons by these compounds. In the fourth aim, antitussive drugs will be delivered intrathecally while monitoring expiratory motor drive during cough to determine the role of spinal pathways in the suppression of expiratory motor discharge. The results of these experiments will provide an important test of the proposed functional organization of the cough pattern generator. Furthermore, this project will test the proposed roles of medullary and spinal cellular elements that contribute to the generation and control of expiratory motor discharge during cough.